Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, 68159 Mannheim, Germany.
J Neurosci. 2013 Apr 17;33(16):7050-6. doi: 10.1523/JNEUROSCI.3081-12.2013.
Neural plasticity is crucial for understanding the experience-dependent reorganization of brain regulatory circuits and the pathophysiology of schizophrenia. An important circuit-level feature derived from functional magnetic resonance imaging (fMRI) is prefrontal-hippocampal seeded connectivity during working memory, the best established intermediate connectivity phenotype of schizophrenia risk to date. The phenotype is a promising marker for the effects of plasticity-enhancing interventions, such as high-frequency repetitive transcranial magnetic stimulation (rTMS), and can be studied in healthy volunteers in the absence of illness-related confounds, but the relationship to brain plasticity is unexplored. We recruited 39 healthy volunteers to investigate the effects of 5 Hz rTMS on prefrontal-hippocampal coupling during working memory and rest. In a randomized and sham-controlled experiment, neuronavigation-guided rTMS was applied to the right dorsolateral prefrontal cortex (DLPFC), and fMRI and functional connectivity analyses [seeded connectivity and psychophysiological interaction (PPI)] were used as readouts. Moreover, the test-retest reliability of working-memory related connectivity markers was evaluated. rTMS provoked a significant decrease in seeded functional connectivity of the right DLPFC and left hippocampus during working memory that proved to be relatively time-invariant and robust. PPI analyses provided evidence for a nominal effect of rTMS and poor test-retest reliability. No effects on n-back-related activation and DLPFC-hippocampus resting-state connectivity were observed. These data provide the first in vivo evidence for the effects of plasticity induction on human prefrontal-hippocampal network dynamics, offer insights into the biological mechanisms of a well established intermediate phenotype linked to schizophrenia, and underscores the importance of the choice of outcome measures in test-retest designs.
神经可塑性对于理解大脑调节回路的经验依赖性重组以及精神分裂症的病理生理学至关重要。功能磁共振成像 (fMRI) 得出的一个重要的回路水平特征是工作记忆期间的前额叶-海马种子连通性,这是迄今为止精神分裂症风险的最佳中间连通性表型。该表型是增强可塑性干预(如高频重复经颅磁刺激 (rTMS))效果的有希望的标志物,并且可以在没有与疾病相关的混杂因素的情况下在健康志愿者中进行研究,但与大脑可塑性的关系尚未得到探索。我们招募了 39 名健康志愿者,以研究 5 Hz rTMS 对工作记忆和休息期间前额叶-海马耦合的影响。在随机和假对照实验中,导航引导 rTMS 应用于右侧背外侧前额叶皮层 (DLPFC),并使用 fMRI 和功能连通性分析(种子连通性和心理生理交互 (PPI))作为读出。此外,还评估了工作记忆相关连通性标志物的测试-重测可靠性。rTMS 引起工作记忆期间右侧 DLPFC 和左侧海马的种子功能连通性显著降低,证明其具有相对的时间不变性和稳健性。PPI 分析为 rTMS 的名义效应和较差的测试-重测可靠性提供了证据。未观察到 n-back 相关激活和 DLPFC-海马静息状态连通性的影响。这些数据首次提供了关于可塑性诱导对人类前额叶-海马网络动力学的影响的体内证据,为与精神分裂症相关的已建立的中间表型的生物学机制提供了深入的了解,并强调了在测试-重测设计中选择结果测量的重要性。